Creatine is an endogenous nutrient occurring in a various mammalian tissues, for example, in the liver, kidneys, muscular tissue, brain tissue, blood and appears as well in the free form as in the form of creatine phosphate. Creatine is considered in a capacity of a remedy enhancing an energetic tissue metabolism, increasing an energetic reserve of ATP first of all in muscle and nerve cells.
Creatine phosphate (CrP) maintains ATP level upon increasing of energy consumption in a cell i.e. takes part in a physiological process of ADP phosphorylation with ATP formation. Among with glycogen CrP is one of main source of high-energy phosphates transformation cycle and so participates in an oxidative phosphorylation of glucose that provides an energy evolution essential for muscular tissue cells activity including skeletal muscles and cardiac muscle.
Because of creatine phosphate is able to provide ATP biosynthesis an increasing of creatine amount in muscles increases a muscular supply of creatine phosphate, enhances an energetic tissue metabolism, enhances a muscles performance capability (tolerance), increases a muscles mass.
Creatine phosphate and creatine are also an allosteric regulators of cell processes (N. Brustovetsky et al., J. Neurochem. 2001. 76. 425-434). Thus administration of 20-30 g of creatine monohydrate per day for a few days leads to increasing of total creatine content in human skeletal muscles by more than 20%. Given properties attract the special attention in view of possibility to use creatine in a capacity of nutritional supplement for organism strengthening and increasing of performance capability. Thus administration of creatine monohydrate in an amount of 15 g per day for at least 2 days is used for an increasing the muscle performance ability (WO/94/002127).
Creatine and creatine phosphate find a wide application in medicine. Thus, creatine, creatine phosphate and cyclocreatine (U.S. Pat. No. 6,706,764) are recommended for a treatment of nervous system diseases such as diabetic and toxic neuropathies, Alzheimer's disease, Parkinson's disease, stroke, etc, metabolism disturbances such as hyperglycaemia and diabetes mellitus (U.S. Pat. No. 6,193,973). Per os administration of creatine is described for a treatment of cardiac insufficiency (WO/EP 97/06225), asthma (U.S. Pat. No. 6,093,746).
Application of creatine phosphate was shown for a treatment of cardio-vascular diseases, prospectivity for a treatment of new-growth tissue (U.S. Pat. No. 5,219,846). In the mean time application of creatine and creatine phosphate are limited by bad solubility and stability in aqueous media at physiological pH values (RU 2 295 261).
Even more creatine is badly adsorbs from gastro-intestinal tract, extent of absorbtion consists a 1 to 14%. It makes necessary an administration of creatine in a high doses. For the purpose of creatine application was effective a composition manufactured at the present time is administered in amount of 20 g per day. In the mean time along with increasing of the cost of therapy administration of a high doses of creatine can lead to negative after-effects for an organism—nitrogen exchange deficit, gastro-intestinal diseases, diarrhea etc.
Therefore a preparation of creatine derivatives possessing the more stability or the more biological activity is of main interest that allows from the one hand to decrease a dose of administered compound and from another hand to find out a new field of application. Herein derivatives of creatine and variable organic acids attract the highest interest.
Thus it is known that application of creatine pyruvates (U.S. Pat. No. 6,166,249; RU 2 114 823) for an enhancement of working efficiency, body weight decreasing, adaptation to oxygen insufficiency associated with ischemia, in a capacity of nutritional supplement, for a protection of skin aging and sun light action (U.S. Pat. No. 7,186,754), for a treatment of female sexual disorders, in particular, dismenorrhea (U.S. Pat. No. 6,503,951).
Derivatives of creatine and malonic, maleic, fumaric, orotic acids and taurine (U.S. Pat. No. 6,838,562; U.S. Pat. No. 6,861,554; U.S. Pat. No. 6,166,249; U.S. Pat. No. 7,109,373) are indicated for nutritional care as a food supplement; creatine citrate (US 2004/077719) is recommended in a capacity of nootropic agent.
One of the most perspective derivatives of creatine comprises amides of creatine of general formula NH═C(NH2)-N(CH3)-CH2-CO-NH-R*X, wherein R is aminoacids residue or protected aminoacids residue; X-organic or mineral acid or water (RU 2 354 645) synthesized and studied by authors.
As it was determined in a process of experiments synthesized amides of creatine possessed an increased solubility and stability in aqueous solutions that allows to use it more wide in a capacity of creatine resource in an organism.
Method preparation of similar amides of creatine comprising of the most close to the claimed one upon achieved effect consist of interaction a deprotected and protected guanidilating agents with amides of sarcosine in polar organic solvents at a temperature not more than 50° C. Preparation of another derivatives of aminoacids is possible based on amides of sarcosine by using a standard chemical reactions described in literature (A. A. Gershkovich, V. K. Kibirev “Peptide Synthesis. Reagents and Methods. Kiev. “Naukova dumka”. 1987).
The disadvantage of given method are multistaging, associated with requirement amides of sarcosine preliminary preparation, insufficiently high yield of desired product which in particular for Creatinyl-Glycine Benzyl Ester Hydrochloride consists of about 5%.